NM_000527.5(LDLR):c.1463T>C (p.Ile488Thr) AND Familial hypercholesterolemia

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Sep 21, 2023
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000791391.7

Allele description [Variation Report for NM_000527.5(LDLR):c.1463T>C (p.Ile488Thr)]

NM_000527.5(LDLR):c.1463T>C (p.Ile488Thr)

Gene:

LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_000527.5(LDLR):c.1463T>C (p.Ile488Thr)

HGVS:

NC_000019.10:g.11113639T>C
NG_009060.1:g.29259T>C
NM_000527.5:c.1463T>CMANE SELECT
NM_001195798.2:c.1463T>C
NM_001195799.2:c.1340T>C
NM_001195800.2:c.959T>C
NM_001195803.2:c.1082T>C
NP_000518.1:p.Ile488Thr
NP_000518.1:p.Ile488Thr
NP_001182727.1:p.Ile488Thr
NP_001182728.1:p.Ile447Thr
NP_001182729.1:p.Ile320Thr
NP_001182732.1:p.Ile361Thr
LRG_274t1:c.1463T>C
LRG_274:g.29259T>C
LRG_274p1:p.Ile488Thr
NC_000019.9:g.11224315T>C
NM_000527.4:c.1463T>C
c.1463T>C

Protein change:

I320T

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000799;

Molecular consequence:

NM_000527.5:c.1463T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1463T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1340T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.959T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1082T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

Recent activity

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NP_312706 (1)
Identical Protein Groups
Coelorinchus polli voucher CAS:Ich:223427 recombination activating protein 1 (RA...
Coelorinchus polli voucher CAS:Ich:223427 recombination activating protein 1 (RAG1) gene, partial cds
gi|227463499|gb|FJ215223.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000823891	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Sep 21, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10978268, 20236128, 23375686, 11810272, 28492532
SCV004358530	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 11, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11810272, 26020417, 31893465, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000823891

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Sep 21, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV004358530

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 11, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Clinical expression of familial hypercholesterolemia in clusters of mutations of the LDL receptor gene that cause a receptor-defective or receptor-negative phenotype.

Bertolini S, Cantafora A, Averna M, Cortese C, Motti C, Martini S, Pes G, Postiglione A, Stefanutti C, Blotta I, Pisciotta L, Rolleri M, Langheim S, Ghisellini M, Rabbone I, Calandra S.

Arterioscler Thromb Vasc Biol. 2000 Sep;20(9):E41-52.

PubMed [citation]

PMID:: 10978268

Mutation detection rate and spectrum in familial hypercholesterolaemia patients in the UK pilot cascade project.

Taylor A, Wang D, Patel K, Whittall R, Wood G, Farrer M, Neely RD, Fairgrieve S, Nair D, Barbir M, Jones JL, Egan S, Everdale R, Lolin Y, Hughes E, Cooper JA, Hadfield SG, Norbury G, Humphries SE.

Clin Genet. 2010 Jun;77(6):572-80. doi: 10.1111/j.1399-0004.2009.01356.x. Epub 2010 Mar 13.

PubMed [citation]

PMID:: 20236128

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000823891.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ile488 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 10978268, 20236128, 23375686), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. ClinVar contains an entry for this variant (Variation ID: 251857). This missense change has been observed in individual(s) with familial hypercholesterolemia and/or hypercholesterolemia (PMID: 11810272; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 488 of the LDLR protein (p.Ile488Thr).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV004358530.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant (also known as p.Ile467Thr in the mature protein) replaces isoleucine with threonine at codon 488 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a few individuals affected with hypercholesterolemia (PMID: 11810272, 26020417, 31893465). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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